A PoleP286R mouse model of endometrial cancer recapitulates high mutational burden and immunotherapy response

Hao Dong Li, Changzheng Lu, He Zhang, Qing Hu, Junqiu Zhang, Ileana C. Cuevas, Subhransu S. Sahoo, Mitzi Aguilar, Elizabeth G. Maurais, Shanrong Zhang, Xiaojing Wang, Esra A. Akbay, Guo Min Li, Bo Li, Prasad Koduru, Peter Ly, Yang Xin Fu, Diego H. Castrillon

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.

Original languageEnglish (US)
Article numbere138829
JournalJCI Insight
Volume5
Issue number14
DOIs
StatePublished - Jun 23 2020

ASJC Scopus subject areas

  • Medicine(all)

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